The precise therapeutic mechanisms of action of antidepressant drugs in relieving depression remain unknown. Antidepressant drugs relieve symptoms in depressed persons, but do no elevate mood in normal, non-depressed persons. Thus, understanding which neurochemical effects of antidepressant drugs are functionally related to their therapeutic efficacy is facilitated by research using behavioral animal models of clinical depression. The learned helplessness model can be used to study the mechanism of action of antidepressant drugs in animals exhibiting behavioral despair. In this proposal we will examine neurochemical changes in the limbic system and other brain regions associated with developing behavioral depression after inescapable stress, and neurochemical changes that occur following normalization of behavior by antidepressant drug treatments. The noradrenergic system serves a key role in the stress response, and in clinical depression. There is strong evidence that the alpha-2 adrenoceptor (o2AR) system is altered in depressed patients, and furthermore studies in normal, non- stressed, animals have established a theoretical framework for o2AR regulation as an important mechanism in the antidepressant response. However, a2AR function has not been systematically studied in the learned helplessness animal model of depression. The central hypothesis is that a2AR receptor function is integral to mechanisms by which antidepressant drugs prevent and reverse behavioral depression. In the clinical setting, antidepressant drugs with different initial biochemical effects are nonetheless equally efficacious in relieving depressive symptoms. Two antidepressant drugs with selectivity for norepinehrine and serotonin re-uptake inhibition will be used to prevent and to reverse learned helpless behavior. It is hypothesized that drugs with different primary mechanisms of action will exert similar effects on a2AR function in brain regions of animals exhibiting learned helpless behavior. Alternatively different drug classes may normalize helpless behavior via different mechanisms and/or in different brain regions. The generalizability of a2AR receptor mechanisms in antidepressant drug action will be tested by comparing the learned helplessness model and the forced swim test model. The role of a2AR in stress induced behavioral depression and antidepressant drug mechanisms will be studied in specific brain regions by 1) biochemical studies of receptor function using quantitative autoradiography for receptor binding levels, receptor affinity state, and receptor coupling to G proteins, and 2) direct infusion of a2AR specific agonist and antagonist drugs into brain regions where o2AR may be critical to normalizing behavior by antidepressant drug treatment. The long term goal is to develop an understanding of antidepressant drug action in clinical depression using animal models. This research should inform future studies in the regulation and alteration of neurotransmitter interactions important in depressive disorders and the mechanisms of therapeutic action for antidepressant drugs.